Synthesis and characterization of copper(II) complexes of pyridine-2-carboxamidrazones as potent antimalarial agents

Article abstract of DOI:10.1016/S0020-1693(03)00047-1

Copper(II) complexes of some pyridine-2-carboxamidrazones have been prepared and characterized. The crystal structures of the copper complex cis-[dichloro(N¹-2-acetylthiophene-pyridine-2-carboxamidrazone) copper(II)] 8a and one of the free ligands, viz. {(p-chloro-2-thioloxy-benzylidine-pyridine-2-carboxamidrazone)} 6, have been determined. The former shows a highly distorted square planar geometry around copper, with weak intermolecular coordination from the thiophenyl sulfur resulting in a stacking arrangement in the crystal lattice. The in vitro activities of the synthesized compounds against the malarial parasite Plasmodium falciparum are reported for the first time, which clearly shows the advantage of copper complexation and the requirement of four coordinate geometry around copper as some of the key structural features for designing such metal-based antimalarials.

Full text of DOI:10.1016/S0020-1693(03)00047-1

Inorganica Chimica Acta 349 (2003) 23Á29
/
www.elsevier.com/locate/ica
Synthesis and characterization of copper(II) complexes of pyridine-2-
carboxamidrazones as potent antimalarial agents
Nikhil H. Gokhale a, Subhash B. Padhye a,*, David C. Billington b,
Daniel L. Rathbone b, Simon L. Croft c, Howard D. Kendrick c,
Christopher E. Anson d, Annie K. Powell d
a Department of Chemistry University of Pune, Pune 411007, India
b Pharmaceutical Sciences Institute, Aston University, Aston Triangle, Birmingham B4 7ET, UK
c Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT UK
d Institut fur anorganische Chemie, Universitat Karlsruhe, Engesserstrasse Geb. 30.45, D-76128 Karlsruhe, Germany
¨
¨
Received 20 July 2002; accepted 26 November 2002
Abstract
Copper(II) complexes of some pyridine-2-carboxamidrazones have been prepared and characterized. The crystal structures of the
copper complex cis-[dichloro(N1-2-acetylthiophene-pyridine-2-carboxamidrazone)copper(II)] 8a and one of the free ligands, viz.
{(p-chloro-2-thioloxy-benzylidine-pyridine-2-carboxamidrazone)} 6, have been determined. The former shows a highly distorted
square planar geometry around copper, with weak intermolecular coordination from the thiophenyl sulfur resulting in a stacking
arrangement in the crystal lattice. The in vitro activities of the synthesized compounds against the malarial parasite Plasmodium
falciparum are reported for the first time, which clearly shows the advantage of copper complexation and the requirement of four
coordinate geometry around copper as some of the key structural features for designing such metal-based antimalarials.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Copper; Carboxamidrazones; Plasmodium falciparum; Antimalarial
1. Introduction
Malaria remains the most serious and refractory
health hazard amongst the parasitic diseases, responsi-
ble for over 200 million infections and 3 million deaths
annually [1]. According to WHO estimates 40% of the
Heterocyclic thiosemicarbazones such as 2-acetylpyr-
world population presently lives under malarial threat
idine thiosemicarbazones (1) have been shown to possess
[2]. The situation is made even worse by the fact that the
potent antimalarial activity [4]. The carboxamidrazones
parasitic organism responsible for the disease viz.
(2) bear a close structural resemblance to these thiose-
Plasmodium falciparum has acquired resistance against
micarbazone compounds and have shown promising
most of the antimalarial agents used clinically [3]. There
antitumor properties upon metal conjugation [5,6]. As a
is thus an urgent need to develop new effective and
selective antimalarial drugs.
logical extension of these findings we have undertaken a
systematic study of the antimalarial activities of these
compounds and the present report describes the synth-
esis, crystal structure determination and antimalarial
activity of a series of pyridine-2-carboxamidrazone
derivatives and their copper(II) complexes against P.
falciparum.
* Corresponding author. Tel.: ꢀ
1728.
E-mail address: sbpadhye@chem.unipune.ernet.in (S.B. Padhye).
/
91-20-569 6061; fax: ꢀ91-20-569
/
0020-1693/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0020-1693(03)00047-1

24
N.H. Gokhale et al. / Inorganica Chimica Acta 349 (2003) 23Á29
/
2. Experimental
rotating anode source, and a deep brown crystal of 8a
using a Stoe IPDS area detector diffractometer, in both
cases using graphite-monochromatised Mo Ka radia-
tion. Both crystals were cooled to 200 K. Both the
structures were solved by direct methods, and refined
against F2 (all data, anisotropic thermal parameters for
all non-H atoms and isotropic for H atoms), using the
SHELXTL software suite [8]. Crystal data and numerical
parameters for the structural refinements are summar-
ized in Table 2.
2.1. Materials
Benzyloxybenzilidene-pyridine-2-carboxamidrazone
(3), t-butylbenzylidine-pyridine-2-carboxamidrazone
(4), naphthylidine-pyridine-2-carboxamidrazone (5), p-
chlorothioloxy-benzylidine-pyridine-2-carboxamidra-
zone (6), 2-acetylpyridine-pyridine-2-carboxamidrazone
(7), 2-acetylthiophene-pyridine-2-carboxamidrazone (8)
were synthesized according to the procedures described
previously [6,7]. Single crystals of 6, suitable for X-ray
diffraction studies, were grown from methanol. Copper
chloride dihydrate was the product of Qualigens Ltd.
(India). Solvents used were distilled prior to their use.
2.5. In vitro antimalarial activity against P. falciparum
3D7 strain
P. falciparum 3D7 [9] cultures were maintained in
RPMI 1640 medium at 37 8C, 5% CO2 at 5% hemato-
crit. Synchronized ring stage cultures were prepared by
15% sorbitol synchronization and diluted to 1% para-
sitemia. A 50 ml of the culture was added per well to 96
well plates in triplicate. Stock solutions of the test
compounds, plus control drugs were prepared at a
concentration of 20 mg mlꢁ1 in DMSO. Compounds
were tested in threefold serial dilution series with
triplicate at each concentration in 96 well plates, the
highest concentration being 30 mg mlꢁ1. After 24 h
incubation [3H] hypoxanthine was added (0.2 mCi per
well) and the plates were incubated for further 24 h.
ED50 values were calculated from [3H] hypoxanthine
uptake as described previously [10].
2.2. Physical measurements
Elemental analyses were carried out in the Micro-
analytical Lab of University of Pune and at Butterworh
Laboratories Ltd., Teddington, UK. IR spectra were
recorded as KBr discs in the range of 4000Á
on a Mattson 3000 FTIR spectrophotometer. Electronic
spectra in the range 200Á1100 nm were recorded on a
Spectronic Genesys-2 machine. The EPR spectra were
recorded on a Varian E109 spectrometer at 300 K using
DPPH compound as a calibrant. The magnetic suscept-
ibilities of the copper complexes were measured at 300 K
on a Faraday balance having field strength of 7000 G.
Cyclic voltammetric measurements were made in DMF
solvent on a Bioanalytical System BAS CV-27 instru-
ment with an XY recorder using Pt disc as the working
electrode against SCE and Pt wire as an auxiliary
electrode. Tetraethyl ammonium perchlorate (TEAP)
was used as a supporting electrolyte
/
500 cmꢁ1
/
3. Results and discussion
The interaction of pyridine-2-carboxamidrazones
with copper chloride in 1:1 molar ratio in ethanol results
in the monomeric copper complexes in good yields and
purity as revealed from the microanalyses (Table 1).
2.3. Synthesis of copper(II) complexes
The copper complexes were synthesized according to
the method described earlier for complexes 3a, 7a and 8a
(Scheme 1) [5,6]. Typically, the pyridine-2-carboxami-
drazone ligand and copper chloride dihydrate were
reacted in 1:1 molar ratio in ethanol for 1 h under
reflux. After leaving the reaction mixture to cool, the
product obtained was collected by filtration and dried
under vacuum. The deep brown rectangular crystals of
the complex 8a suitable for single crystal X-ray diffrac-
tion studies were obtained upon recrystallizing the
compound from acetonitrile. The analytical data on
the copper complexes are summarized in Table 1.
3.1. Crystal structure of 6
The molecular structure of the ligand 6 with number-
ing scheme is shown in Fig. 1, while the selected bond
distances and angles are listed in Table 3. The bond
lengths indicate that within the central chain of the
molecule, the C(7)Ã
/
N(4) and C(6)Ã
/
N(3) linkages have
largely double bond character, comparable with those
found in previously reported structures [11]. The two
double bonds display E and Z stereoisomerism, respec-
tively, as would be expected in order to prevent the
unfavourable steric interactions between CÃ
/H bonds
and nitrogen lone pairs. The unit consisting of the
amidrazone chain and the pyridyl and phenyl rings are
largely planar, with the largest deviation observed for
2.4. X-ray crystallography of the ligand 6 and copper
complex 8a
N(2) and S(1) from the mean plane being 0.364(1) and
˚
Data were measured on a yellow crystal of 6 using a
Bruker SMART Apex CCD diffractometer with a
0.287(1) A, respectively. The torsion angle C(12)Ã
/
C(13)Ã
/
S(1)ÃC(14) is found to be 77.39(13)8, indicating
/

N.H. Gokhale et al. / Inorganica Chimica Acta 349 (2003) 23Á
/29
25
Scheme 1. Copper(II) complexes of pyridine-2-carboxamidrazones.
that the p-chlorophenyl ring has rotated in such a way
as to make it nearly perpendicular to the amidrazone
plane thereby preventing the unfavourable steric inter-
actions.
and is best described as a highly distorted square planar
geometry. Although the two CuÃN distances are
similar, as are also the CuÃCl distances, the chlorides
are nearly equally displaced above (1.184(6) A for Cl(1))
/
/
˚
˚
and below (1.136(6) A for Cl(2)) the plane constituted
by the atoms containing NCCNCu. The dihedral angle
between this plane and the planes comprising the CuCl2
is found to be 43.74(12)8. The driving force for this
distortion appears to be the steric effect exercised by the
bulky methyl group at C(8), which is displaced out of
the amidrazone plane away from the chloride, Cl(2). A
3.2. Crystal structure of 8a
The molecular structure of the copper complex 8a
with the numbering scheme is shown in Fig. 2. Selected
bond distances and angles are given in Table 4. The
structure of this complex shows it to be a mononuclear
complex with the ligand 8 acting as a bidentate N,N
donor moiety. The pyridyl N(1) and diazine N(3)
nitrogens of the ligand coordinate to the central copper
atom (Cu(1)) forming a five-membered chelate ring
through the rotation of the pyridyl group by 1808
˚
weak intermolecular contact, 3.510(2) A, is observed
between the Cu(1) and S(1) atoms of the adjacent
molecule at {xꢁ
/
1/2, ꢁ
/
yꢀ
/
3/2, ꢁ
/
zꢀ1}, resulting in the
/
stacking of the molecules in the crystal lattice (Fig. 2).
This stacking is reinforced by hydrogen bonding be-
tween the free amino group, N(2), and the chloride
ligands of the adjacent complex molecules (Table 5).
around the C(5)Ã
/
C(6) linkage. The coordination sphere
around Cu(1) is completed by the two chloride ligands,
Table 1
Analytical data on the copper complexes (3aÁ8a)
/
Complex Yield (%) IR (cmꢁ1
)
meff (BM) a UVÁ
/
Vis (nm) b Elemental analyses c
%C %H
E1/2 (V) d
n(NH2)
n(CÄ/N)
%M
3a
4a
5a
6a
7a
8a
78
86
76
92
60
58
3388, 3278, 3224
3416, 3387, 3316
3400, 3276
1628, 1697 1.79
1633, 1601 1.52
1626, 1616 1.54
1635, 1597 1.71
1653, 1560 1.78
1660, 1566 1.85
833, 625
830
842
51.61 (51.71) 3.68 (3.87) 13.48 (13.57)
49.16 (49.27) 4.11 (4.83) 15.18 (15.21)
50.01 (49.23) 3.41 (3.43) 15.44 (15.44)
45.46 (44.60) 3.00 (3.47) 12.82 (12.60
40.83 (41.73) 3.36 (3.47) 16.42 (16.99)
38.60 (38.01) 3.08 (3.16) 16.71 (16.77)
ꢁ
/
0.05
0.10
0.47
0.19
0.26
0.23
ꢀ
/
ꢀ
/
3369, 3270
3342, 3375, 3274
3482, 3352
818
663
ꢀ
/
ꢀ
/
727
ꢀ/
a
b
c
At 300 K.
In DMF.
Values in parentheses are calculated values.
In 0.1 M TEAP containing DMSO (Cuꢀ2/ꢀ1 quasi-reversible couple).
d

26
N.H. Gokhale et al. / Inorganica Chimica Acta 349 (2003) 23Á29
/
Table 2
Crystal data and structure refinements for 6 and 8a
The polycrystalline X-band EPR spectra of the
complexes 3aÁ5a and 6a at room temperature are axial
with g ꢀgÞ and are consistent with the distorted
tetragonal geometry. The spectra of the complexes are
poorly resolved in the g region and lack the metal
/
/
Š
6
8a
Empirical formula
Formula weight
Temperature (K)
C
19H15ClN4S
C12H12Cl2CuN4S
378.76
200(2)
Š
366.86
200(2)
0.71073
hyperfine probably due to dipoleÁdipole interactions
/
between copper atoms of the neighboring molecules.
The complex 6a shows a single isotropic signal in the
solid state, however, its spectrum in DMSO solution
˚
Wavelength (A)
0.71073
Orthorhombic
P212121
7.2684(6)
12.1197(10)
16.3884(16)
90
Crystal system
Space group
Triclinic
¯
P/1
˚
a (A)
7.4095(6)
8.1033(7)
15.8122(13)
83.621(2)
76.612(1)
65.685(1)
841.53(12)
2
exhibits the hyperfine structure in the g region. The g /
A
Š
quotient calculated for this compound (199 cm)
Š
˚
b (A)
Š
˚
c (A)
suggests a distorted tetragonal geometry around copper
[16] which is in good agreement with its electronic
a (8)
b (8)
g (8)
90
90
spectrum. The EPR parameters for complexes 3aÁ
/6a are
3
˚
V (A )
Z
1443.7(2)
4
1.743
listed in Table 6.
The cyclic voltammetric profiles of the copper com-
pounds in DMF solvent show two consecutive reduction
steps, the first corresponding to the Cuꢀ2/ꢀ1 reduction
which is found to be quasi-reversible (Table 1) while the
Dcalc (Mg mꢁ3
)
1.448
0.360
380
m(Mo Ka) (mmꢁ1
F(000)
)
2.020
764
Crystal size (mm)
0.45ꢂ
0.25
2u Range for data collection (8) 2.64Á
/
0.35ꢂ
/
0.15ꢂ
0.10
/
0.10ꢂ
/
second peak observed at ꢁ0.6 V is found to be
/
/
56.10
4.18Á
5729
2823
/
52.34
irreversible and is ascribed to the intra-ligand reduction
processes.
Reflections collected
Independent reflections
Rint
5263
3647
0.0469
99.2%
286
0.0484
99.9%
188
Completeness to 2uꢃ/50.008
Parameters
Goodness-of-fit on F2 (all data) 0.979
3.5. In vitro antimalarial activity
1.015
0.1403
0.0499
wR2 (all data)
0.1027
0.0379
The antimalarial activity of all the compounds were
tested against P. falciparum 3D7 strain and the ED50
(i.e. effective dose at which 50% inhibition of parasite
growth is observed) values of all ligands and their metal
conjugates are summarized in Table 7. An examination
of the results on the ligands reveals the compound 7 as
the most active compound with ED50 value of 0.9
mg mlꢁ1. As explained earlier this ligand bears a close
analogy with the active heterocyclic thiosemicarbazone
antimalarials. The incorporation of the heterocyclic
sulfur (as in 8) or the ortho-thioether side chain (as in
6) on the amidrazone scaffold seems to have very little
influence on the antimalarial activity. It may be inferred
that the presence of a 2-pyridyl-ethylidene moiety
appears to be the most crucial structural motif of the
carboxamidrazone compounds possessing potent anti-
malarial activity.
R1 [I ꢀ2s(I)]
/
Flack x parameter
Maximum difference peak and
Á
ꢀ
ꢁ
/
ꢁ
/
0.01(3)
0.689 and
0.724
/
0.337 and
ꢀ
/
ꢁ3
˚
hole (e A
)
/
0.292
ꢁ/
3.3. Infrared and electronic absorption spectra
All present ligands (3Á
absorption bands around 3300Á
intramolecularly hydrogen bonded Ã
the imino (CÄN) grouping show sharp bands around
1630 and 1590 cmꢁ1. In the copper complexes the bands
due to ÃNH2 are shifted to lower frequencies due to the
loss of intramolecular hydrogen bonding (Table 1) while
N frequencies are shifted to higher
/
8) are found to exhibit strong
3500 cmꢁ1 due to
NH2 group while
/
/
/
/
the imino CÄ
/
frequencies due to back coordination [12].
The electronic spectra of the complexes in DMF
The antimalarial activities of the copper complexes
solvent show broad dÁ
/
d absorption bands around 700Á
/
are found to lie in the concentration range of 0.13Á1.48
/
800 nm characteristic of the distorted octahedral com-
plexes [13]. The broadening of these bands is suggestive
of the solvent coordination [14].
mg mlꢁ1 (except for the complex 7a with ED50 value of
9.40 mg mlꢁ1) clearly indicating the enhancement in the
potency upon copper conjugation. The highest activity is
observed for the complex 8a which exhibits the lowest
ED50 value of 0.13 mg mlꢁ1. It is observed that the four-
coordinate planar geometry is preferred structural
feature in these compounds, which has been suggested
to promote facile internalization by Antholine et al. [17].
The other contributing factor to the enhanced antima-
larial activity of the copper compounds is their positive
reduction potentials which facilitate their reduction to
3.4. Magnetic measurements, EPR spectra and
electrochemistry
The magnetic moments of all copper complexes (3aÁ
8a) are in the range of 1.52Á1.85 BM (Table 1) which are
consistent with the monomeric, planar Cu(II) coordina-
tion compounds [15].
/
/

N.H. Gokhale et al. / Inorganica Chimica Acta 349 (2003) 23Á
/29
27
Fig. 1. Molecular structure of 6 (50% thermal ellipsoids).
Table 5
Table 3
˚
˚
Hydrogen bonds and angles for 8a (A and 8).
Selected bond lengths (A) and angles (8) for ligand 6
DÃ
/
H
/
Á Á Á
/
A
d(DÃ
/
H) d(H
/
Á Á Á
/
A) d(D
/
Á Á Á
/
A)
B(DHA)
/
Bond lengths
C(5)Ã
C(6)Ã
C(6)Ã
N(3)Ã
N(4)Ã
/
C(6)
N(2)
N(3)
1.4831(19) C(7)Ã
1.3416(19) C(13)Ã
1.2917(18) S(1)ÃC(14)
1.3949(16) C(17)ÃCl(1)
1.2661(18)
/
C(8)
1.4659(19)
1.7774(15)
1.7686(15)
1.7396(15)
N(2)Ã
N(2)Ã
/H(21)/
Á Á Á
/
Cl(2b)
Cl(1c)
0.97(8)
0.99(8)
2.32(8)
2.49(8)
3.241(6)
3.409(6)
158(7)
156(6)
/
/
S(1)
/
H(22)Á Á Á
/
/
/
/
/
N(4)
C(7)
/
Symmetry transformations: b {xꢀ
2, ꢁyꢀ1, zꢀ1/2}.
/1/2, ꢁ
/
yꢀ
/
3/2, ꢁ
/
zꢀ
/1}, c {ꢁ
/
xꢀ1/
/
/
/
/
/
Bond angles
N(2)ÃC(6)Ã
N(2)ÃC(6)Ã
N(3)ÃC(6)Ã
C(6)ÃN(3)Ã
/
/
N(3)
C(5)
C(5)
N(4)
126.09(13) N(3)Ã
115.96(13) N(4)Ã
117.95(12) C(13)Ã
111.49(11)
/
N(4)Ã
C(7)Ã
S(1)Ã
/
C(7)
112.92(12)
121.40(13)
102.58(7)
/
/
/
/C(8)
/
/
/
/
C(14)
Table 6
EPR parameters of copper complexes 3aÁ
/
/
/
6a
Compound
EPR parameters a
gÞ
g
Š
[Cu(3)Cl2] 3a
[Cu(4)Cl2] 4a
[Cu(5)Cl2] 5a
[Cu(6)Cl2] 6a
2.16
2.06
2.12
2.11b
2.57
2.13
2.50
2.43, 2.54 b
Table 4
˚
Selected bond lengths (A) and angles (8) for Complex 8a
a
Polycrystalline X-band EPR at room temperature.
In DMSO solution.
Bond lengths
b
Cu(1)Ã
Cu(1)Ã
Cu(1)Ã
Cu(1)Ã
Cu(1)Ã
N(1)Ã
C(5)Ã
C(6)Ã
/
N(1)
N(3)
Cl(1)
Cl(2)
S(1a)
1.986(6)
1.979(6)
C(6)Ã
N(3)Ã
/
N(2)
1.328(9)
1.405(7)
1.284(8)
1.475(9)
1.482(9)
1.700(7)
1.665(8)
/
/
N(4)
C(7)
/
2.2369(19) N(4)Ã
2.2109(18) C(7)Ã
3.510(2)
1.346(8)
1.482(9)
1.304(9)
/
/
/
C(9)
C(8)
S(1)
/
C(7)Ã
/
Cu(I) species intracellularly detrimental to parasite
growth.
/
C(5)
C(9)Ã
/
/C(6)
C(12)ÃS(1)
/
/N(3)
Bond angles
N(1)ÃCu(1)Ã
N(1)ÃCu(1)Ã
N(3)ÃCu(1)Ã
N(1)ÃCu(1)Ã
N(3)ÃCu(1)Ã
/
/
N(3)
Cl(2)
Cl(2)
Cl(1)
Cl(1)
81.2(2)
Cl(1)Ã
Cu(1)Ã
Cu(1)Ã
Cl(1)ÃCu(1)Ã
145.17(17) Cl(2)ÃCu(1)Ã
/
Cu(1)Ã
/
Cl(2)
98.05(7)
76.68(16)
84.99(16)
128.59(7)
74.41(6)
/
/
150.76(16) N(1)Ã
100.42(16) N(3)Ã
96.46(17)
/
/
S(1a)
S(1a)
S(1a)
S(1a)
4. Conclusion
/
/
/
/
/
/
/
/
The present work has shown that copper conjugation
of the carboxamidrazone ligands results in their en-
hanced antimalarial activities against P. falciparum 3D7
/
/
/
/
Symmetry transformation: a {xꢁ
/
1/2, ꢁ
/
yꢀ
/
3/2, ꢁ
/
zꢀ1}.
/

28
N.H. Gokhale et al. / Inorganica Chimica Acta 349 (2003) 23Á29
/
Fig. 2. Molecular Structure of [Cu(8)Cl2] 8a with intermolecular CuÁS interactions.
/
Table 7
In vitro antimalarial activity of pyridine-2-carboxamidrazones and
their copper complexes against P. falciparum 3D7 strain a
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK, (fax: ꢀ44-1223-336-033 or e-mail: deposit@ccdc.
cam.ac.uk).
/
Compound
ED50 values (mg mlꢁ1
)
3(Rꢃ
4(Rꢃ
5(Rꢃ
6(Rꢃ
7(Rꢃ
8(Rꢃ
[Cu(3)Cl2] 3a
[Cu(4)Cl2] 4a
[Cu(5)Cl2] 5a
[Cu(6)Cl2] 6a
[Cu(7)Cl2] 7a
[Cu(8)Cl2] 8a
/
H, Arꢃ
H, Arꢃ
H, Arꢃ
H, Arꢃ
Me, Arꢃ
Me, Arꢃ
/
2-OCH2Ph-Ph)
4-t-Bu-Ph)
naphthyl)
3.50
2.70
3.50
7.30
0.90
Acknowledgements
/
/
/
/
NHG acknowledges CSIR (New Delhi, India) for
Senior Research Fellowship (SRF). This investigation
also received financial support from UNDP/World
Bank/WHO Special Programme for Research and
Training in Tropical Diseases (TDR). SBP would like
to thank the British Council, India, for the visitorship
under the HE link program.
/
/
4-Cl-2S-Ph-Ph)
/
/2-acetylpyridine)
/
/2-acetylthiophene)
ꢀ/
30
1.25
0.44
1.48
1.09
9.40
0.13
0.01
Chloroquine (standard compound)
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